Elevated Liver Stiffness Measurement Research Articles

Early detection of liver disease in patients with alcohol use disorder improves long-term abstinence.

Excessive alcohol consumption is a major global health concern, contributing to millions of deaths annually and a significant proportion of cirrhosis cases; however, standardized protocols for early identification of alcohol-associated liver disease are lacking. In this retrospective cohort study, we aimed to understand the prevalence and risk factors associated with elevated liver stiffness measurement (LSM) in high-risk patients with alcohol use disorder (AUD) and identify variables associated with longitudinal abstinence and outcomes. Veterans with severe AUD without known liver disease admitted to a 35-day residential substance use treatment program were offered liver health screening, including Fibroscan evaluation. Assessment of AUD severity and liver health outcomes were evaluated longitudinally by chart review. In a cohort of 257 veterans with severe AUD admitted to residential treatment, 185 underwent Fibroscan evaluation, and 22 were identified to have elevated LSM concerning for compensated advanced chronic liver disease. Patients with elevated LSM were more likely to remain abstinent after 1 year. About 41% of patients with LSM ≥ 10kPa (5% of all screened patients) were confirmed to have cirrhosis on follow-up and incorporated into routine hepatology care. Screening of liver disease in high-risk populations with non-invasive imaging modalities provides an opportunity to identify patients at risk for compensated advanced chronic liver disease before decompensation. Identification of increased risk for advanced chronic liver disease may promote abstinence in patients with severe AUD. Collaboration between mental health professionals and hepatologists is critical for the integration of care for patients with AUD and liver disease.

Common variable immunodeficiency disorder-related liver disease is common and results in portal hypertension and an increased risk of death.

Common variable immunodeficiency disorder (CVID) manifests with recurrent infections and inflammatory complications, including liver disease. We report the clinical features, natural history, and outcomes of patients with CVID-related liver disease (CVID-rLD) from a tertiary immunology and hepatology center. Two hundred eighteen patients were identified; CVID-rLD was defined by persistently abnormal liver function tests or evidence of chronic liver disease (CLD) or portal hypertension (PHTN) by radiological or endoscopic investigation, after exclusion of other causes. Patients with CVID-rLD were investigated and managed following a joint pathway between immunology and hepatology services. Data, including clinical parameters, investigations, and outcomes, were retrospectively collected. A total of 91/218 (42%) patients had evidence of CVID-rLD, and 40/91 (44%) had PHTN. Patients with CVID-rLD were more likely to have other noninfectious complications of CVID (85/91, 93.4% vs. 75/127, 59.1%, p<0.001) including interstitial lung disease, gut disease, and autoimmune cytopenias. Nodular regenerative hyperplasia (NRH) was identified in 63.8% of liver biopsies, and fibrosis in 95.3%. Liver stiffness measurements (LSMs) were frequently elevated (median 9.95 kPa), and elevated LSM was associated with PHTN. All-cause mortality was higher in those with CVID-rLD (24/91, 26.4% vs. 14/127, 11%, p=0.003), which was the only organ complication associated with mortality (HR 2.24, 1.06-4.74, p=0.04). Factors predicting mortality in CVID-rLD included PHTN, increasing fibrosis, and LSM. Liver disease is a common complication of CVID as part of complex, multi-organ involvement and is associated with high rates of PHTN and an increased hazard of mortality.

Lower prevalence of elevated liver stiffness measurements in people with type 2 diabetes taking sodium-glucose co-transporter 2 inhibitors or glucagon-like peptide-1 receptor agonists

Introduction and ObjectivesAmong people with type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) is very common and has an increased risk of clinically significant liver disease. The use of sodium-glucose co-transporter 2 (SGLT2i) inhibitors and glucagon-like peptide-1 (GLP-1a) receptor agonists is endorsed to reduce major cardiovascular events and/or progression of chronic kidney disease. Their prevalence of use in people with T2D and co-existent NAFLD remains unclear. We sought to determine the prevalence of use of these medications at two different time periods, and their association with prevalence of clinically significant liver disease. Materials and MethodsConsecutive people with type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) were recruited from diabetes clinics between Jun-2021 and Jun-2022 (‘current’ cohort). Liver stiffness measurements (LSM) using FibroScan were performed. Medication data were collected prospectively at recruitment and verified with the dispensing pharmacy or general practitioner medical records. Data for a historical cohort with NAFLD and T2D recruited from the same clinics during 2015–2017 (‘historical’ cohort) were available. Logistic regression was used to evaluate factors associated with LSM <8.0 or ≥8 kPa (clinically significant fibrosis). ResultsThere were 292 participants, 177 in the historical cohort and 115 in the current cohort. In the current cohort, 57.4% of patients with T2D and NAFLD were taking a GLP-1a and 42.6% were taking a SGLT2i; a 2.6 to 3.4-fold higher prevalence than in 2015–2017. A lower proportion of the current cohort (23.9% compared to 38.4%) had clinically significant fibrosis (LSM ≥8 kPa; p = 0.012). When the cohorts were pooled and differences adjusted for in multivariable logistic regression analysis, patients taking a GLP-1a or a SGLT2i were 2 times more likely to have a lower LSM (<8 kPa) compared to patients not taking these drugs (OR=2.05, 95%CI 1.07–3.94, p = 0.03 and OR 2.07 95%CI 1.04–4.11, p = 0.04, respectively). ConclusionsThe observation of a lower LSM in people taking SGLT2i and/or GLP-1a following adjustment for other relevant clinico-demographic variables provides support for clinical trials to assess their efficacy in reducing the progression of NAFLD.

Prevalence, risk factors and diagnostic accuracy of non-invasive tests for NAFLD in people with type 1 diabetes

Background & AimsThe epidemiology of non-alcoholic fatty liver disease (NAFLD) in people with type 1 diabetes (T1D) is not yet elucidated. This study aimed to assess the diagnostic accuracy of non-invasive tests for NAFLD, to investigate the prevalence and severity of NAFLD, and to search for factors contributing to NAFLD in people with T1D. MethodsIn this prospective cohort study, we consecutively screened 530 adults with T1D from a tertiary care hospital, using ultrasound (US), vibration-controlled transient elastography equipped with liver stiffness measurement (LSM) and controlled attenuation parameter, and the fatty liver index. Magnetic resonance spectroscopy (MRS) was performed in a representative subgroup of 132 individuals to validate the diagnostic accuracy of the non-invasive tests. ResultsBased on MRS as reference standard, US identified individuals with NAFLD with an AUROC of 0.98 (95% CI 0.95–1.00, sensitivity: 1.00, specificity: 0.96). The controlled attenuation parameter was also accurate with an AUROC of 0.85 (95% CI 0.77–0.93). Youden cut-off was ≥270 dB/m (sensitivity: 0.90, specificity: 0.74). The fatty liver index yielded a similar AUROC of 0.83 (95% CI 0.74–0.91), but the conventional cut-off used to rule in (≥60) had low sensitivity and specificity (0.62, 0.78). The prevalence of NAFLD in the overall cohort was 16.2% based on US. Metabolic syndrome was associated with NAFLD (OR: 2.35 [1.08–5.12], p = 0.031). The overall prevalence of LSM ≥8.0 kPa indicating significant fibrosis was 3.8%, but reached 13.2% in people with NAFLD. ConclusionsNAFLD prevalence in individuals with T1D is 16.2%, with approximately one in 10 featuring elevated LSM. US-based screening could be considered in people with T1D and metabolic syndrome. Impact and ImplicationsWe aimed to report on the prevalence, disease severity, and risk factors of NAFLD in type 1 diabetes (T1D), while also tackling which non-invasive test for NAFLD is the most accurate. We found that ultrasound is the best test to diagnose NAFLD. NAFLD prevalence is 16.2%, and is associated with metabolic syndrome and BMI. Elevated liver stiffness indicating fibrosis is overall not prevalent in people with T1D (3.8%), but it reaches 13.2% in those with T1D and NAFLD.

Accuracy of FIB-4 to Detect Elevated Liver Stiffness Measurements in Patients with Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study in Referral Centers.

The identification of advanced fibrosis by applying noninvasive tests is still a key component of the diagnostic algorithm of NAFLD. The aim of this study is to assess the concordance between the FIB-4 and liver stiffness measurement (LSM) in patients referred to two liver centers for the ultrasound-based diagnosis of NAFLD. Fibrosis 4 Index for Liver Fibrosis (FIB-4) and LSM were assessed in 1338 patients. A total of 428 (32%) had an LSM ≥ 8 kPa, whereas 699 (52%) and 113 (9%) patients had an FIB-4 < 1.3 and >3.25, respectively. Among 699 patients with an FIB-4 < 1.3, 118 (17%) had an LSM ≥ 8 kPa (false-negative FIB-4). This proportion was higher in patients ≥60 years, with diabetes mellitus (DM), arterial hypertension or a body mass index (BMI) ≥ 27 kg/m2. In multiple adjusted models, age ≥ 60 years (odds ratio (OR) = 1.96, 95% confidence interval (CI) 1.19–3.23)), DM (OR = 2.59, 95% CI 1.63–4.13), body mass index (BMI) ≥ 27 kg/m2 (OR = 2.17, 95% CI 1.33–3.56) and gamma-glutamyltransferase ≥ 25 UI/L (OR = 2.68, 95% CI 1.49–4.84) were associated with false-negative FIB-4. The proportion of false-negative FIB-4 was 6% in patients with none or one of these risk factors and increased to 16, 31 and 46% among those with two, three and four concomitant risk factors, respectively. FIB-4 is suboptimal to identify patients to refer to liver centers, because about one-fifth may be false negative at FIB-4, having instead an LSM ≥ 8 KPa.

Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness.

Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. We collected cross-sectional, clinical data including liver biopsies from a derivation ( n = 48) and a validation cohort ( n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84-0.99). In the validation cohort, plasma TREM2 level increased approximately two-fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77-0.89; p < 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning ( p < 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule-in and rule-out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule-out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule-in cutoff (specificity 89%; sensitivity 54%). Plasma TREM2 is a plausible individual biomarker that can rule-in or rule-out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.

Elastographic parameters of liver steatosis and fibrosis predict independently the risk of incident chronic kidney disease and acute myocardial infarction in patients with type 2 diabetes mellitus

AimsThe aim of this prospective study was to examine the relationship between controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) with the risk of developing a composite endpoint inclusive of incident acute myocardial infarction (AMI), cerebrovascular insult (CVI) or chronic kidney disease (CKD) in people with type 2 diabetes mellitus (T2DM). MethodsThis study included 238 T2DM outpatients without chronic liver diseases. ResultsThe patient population was followed for a median period of 7.6 years. Kaplan-Meier survival analyses showed that there was a higher proportion of patients who developed the aforementioned composite outcome (P < 0.001 by the log-rank test), as well as CKD (P < 0.001) or AMI alone (P = 0.014) among those with elevated CAP values (≥238 dB/m) at baseline. Similarly, Kaplan-Meier survival analyses showed that there was a higher proportion of patients who developed the composite outcome (P < 0.001), as well as CKD (P < 0.001), or AMI alone (P < 0.001) among those with elevated LSM values (≥7.0/6.2 kPa). In multivariable regression analyses, the presence of elevated CAP (adjusted-hazard ratio 2.34, 95% CI 1.32–4.15) and elevated LSM (adjusted-hazard ratio 2.84, 95% CI 1.92–4.21), independently of each other, were associated with a higher risk of developing the composite outcome, as well as incident AMI or CKD alone after adjusting for traditional cardiovascular risk factors and diabetes-related variables. ConclusionsOur study shows that the elastographic parameters of liver steatosis and fibrosis independently predict the long-term risk of developing chronic vascular complications in T2DM patients.

Prediction of long-term morbidity and mortality after liver transplantation using two-dimensional shear wave elastography compared with liver biopsy.

The role of noninvasive liver disease assessment by two-dimensional shear wave elastography (2D-SWE) to diagnose fibrosis is well described in patients with chronic liver disease. However, its role in prognosis, especially after liver transplantation (LT) has not been adequately examined. We hypothesized that elevated liver stiffness measurement (LSM) as measured by 2D-SWE after LT predicts future morbidity and mortality independent of fibrosis by liver biopsy. In a prospective cohort study, consecutive LT recipients underwent concomitant protocol 2D-SWE and protocol liver biopsy (2012-2014), with the assessor blinded to biopsy findings. We examined the baseline correlation of LSM with fibrosis stage and the association between elevated LSM and the development of subsequent clinical outcomes and all-cause mortality. A total of 187 LT recipients (median age 58years, 38.5% women, median body mass index 26.5 kg/m2 , 55.1% hepatitis C virus, 17.6% nonalcoholic steatohepatitis/cryptogenic) were examined. Median time between LT and biopsy/2D-SWE assessment was 4.0years, and the median follow-up time after LSM determination was 3.5years. Median LSM was 9kPa (8kPa [F0/F1], 11.5kPa [F2], 12kPa [F3/F4]). There was a positive correlation between LSM and fibrosis stage (rs =0.41; p<0.001). LSM ≥11kPa was associated with lower survival within 3years (84.8 vs. 93.7%; p=0.04). After adjusting for age, sex, and fibrosis stage, LSM ≥11kPa was independently associated with mortality (hazard ratio, 2.45; 95% confidence interval, 1.08-5.60). Elevated LSM by 2D-SWE is associated with increased mortality after LT independent of hepatic fibrosis. Given the overall decrease in the use of liver biopsy in the current era, 2D-SWE may serve as a novel noninvasive prognostic tool to predict relevant outcomes late after LT.

Prevalence of Elevated Liver Stiffness Among Potential Candidates for Bariatric Surgery in the United States

PurposeObesity represents a well-known risk factor for metabolic-dysfunction associated fatty liver disease (MAFLD) and its progression towards cirrhosis. The aim of this study is to estimate the proportion of potential candidates to a bariatric surgery intervention that has an elevated liver stiffness on vibration-controlled transient elastography (VCTE).Materials and MethodsThis is a cross-sectional study performed using data obtained during the 2017–2018 cycle of the National Health and Nutrition Examination Survey. Potential candidates for a bariatric surgery intervention from the general US population were identified by applying criteria from international guidelines. All included participants were evaluated by VCTE. A controlled attenuation parameter (CAP) value ≥ 288 dB/m was considered indicative of steatosis while liver stiffness measurement (LSM) was considered elevated if ≥ 9.7 kPa. Multivariable logistic regression models were fitted to identify independent predictors of both outcomes.ResultsA total of 434 participants were included (mean age 42.9 ± 0.6 years; 54.4% women). Among them, 76.7% (95% CI 71.7–81.0) had steatosis, while 23.1% (95% CI 17.8–29.3) had an elevated LSM. Male sex, older age, γ-glutamyltranspeptidase levels, and body mass index (BMI) were independent predictors of steatosis, while BMI was the only independent predictor of elevated LSM. Non-Hispanic black participants were protected from both outcomes, while other ethnicities were not.ConclusionThe prevalence of elevated LSM is high in potential candidates for a bariatric surgery intervention. Accurate screening for occult advanced liver disease might be indicated in this patient population.Graphical abstract

Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population

Fibrosis-4 (FIB-4) and the nonalcoholic fatty liver disease fibrosis score (NFS) are the 2 most popular noninvasive blood-based serum tests proposed for widespread fibrosis screening. We therefore aimed to describe the accuracy of FIB-4 and NFS to detect elevated liver stiffness as an indicator of hepatic fibrosis in low-prevalence populations. This study included a total of 5129 patients with concomitant measurement of FIB-4, NFS, and liver stiffness measurement (LSM) by Fibroscan (Echosens, France) from 5 independent population-based cohorts from Spain, Hong Kong, Denmark, England, and France; 3979 participants from the general population and 1150 from at-risk cohorts due to alcohol, diabetes, or obesity. We correlated LSM with FIB-4 and NFS, and calculated pre- and post-test predictive values of FIB-4 and NFS to detect elevated LSM at 8 kPa and 12 kPa cutoffs. The mean age was 53 ± 12 years, the mean body mass index was 27 ± 5 kg/m2, and 2439 (57%) were women. One in 10 patients (552; 11%) had liver stiffness ≥8 kPa, but 239 of those (43%) had a normal FIB-4, and 171 (31%) had normal NFS. The proportion of false-negatives was higher in at-risk patients than the general population. FIB-4 was false-negative in 11% of diabetic subjects, compared with 2.5% false-negatives with NFS. Waist circumference outperformed FIB-4 and NFS for detecting LSM ≥8 kPa in the general population. Almost one-third (28%-29%) of elevated FIB-4/NFS were false-positive in both the general population and at-risk cohorts. FIB-4 and NFS are suboptimal for screening purposes due to a high risk of overdiagnosis and a non-negligible percentage of false-negatives, especially in patients with risk factors for chronic liver disease. Waist circumference emerged as a potential first step to identify patients at risk for liver fibrosis in the general population.

Liver stiffness and prediction of cardiac outcomes in patients with acute decompensated heart failure.

In acute decompensated heart failure (ADHF), noninvasive markers that predict morbidity and mortality are limited. Liver stiffness measurement (LSM) increases with hepatic fibrosis; however, it may be falsely elevated in patients with ADHF in the absence of liver disease. We investigated whether elevated LSM predicts cardiac outcomes in ADHF. In a prospective study, we examined 52 ADHF patients without liver disease between 2016 and 2017. Patients underwent liver 2D shear wave elastography (SWE) and were followed for 12 months to assess the outcomes of left ventricular assist device (LVAD), heart transplant (HT) or death. The median LSM was elevated in patients who received an LVAD or HT within 30-days compared to those who did not (median [IQR]: 55.6 [22.5 - 63.4] vs 13.8 [9.5 - 40.3] kPa, p=.049). Moreover, the risk of composite outcome was highest in the 3rd tertile (>39.8kPa compared to 1st and 2nd combined, HR 2.83, 95% CI 1.20- 6.67, p=.02). Each 1-kPa increase in LSM was associated with a 1%-increase in the incidence rate of readmissions (IRR 1.01, 95% CI 1.00-1.02, p=.01). LSM may serve as a novel noninvasive tool to determine LVAD, HT, or death in patients with ADHF.

HBV co-infection is associated with persistently elevated liver stiffness measurement in HIV-positive adults: A 6-year single-centre cohort study in Nigeria.

In Nigeria, the effect of Hepatitis B virus (HBV) on long-term liver outcomes in persons with HIV (PLH) has not been described. We determined changes in liver stiffness measure (LSM) using transient elastography over 6years in HIV mono-infected and HIV-HBV co-infected Nigerians initiating antiretroviral therapy (ART) and factors associated with LSM decline. This single centre, cohort study enrolled ART-naïve HIV mono- and HIV-HBV co-infected adults (≥18years) at the APIN Public Health Initiatives-supported HIV Care and Treatment Centre at Jos University Teaching Hospital, Nigeria, from 7/2011 to 2/2012. LSM at baseline, Years 3 and 6 were analysed using longitudinal models to estimate changes over time and their predictors. Data from 100 (31%) HIV-HBV co-infected and 225 (69%) HIV mono-infected participants were analysed. Median LSM at baseline was 6.10 (IQR: 4.60-7.90) kPa in co-infected and 5.10 (IQR: 4.40-6.10) kPa in mono-infected participants. In adjusted analyses, average LSM was not significantly different between Year 0 and 3 (β = 0.02, -0.22 to 0.26, p = 0.87 and Year 0 and 6 (β = -0.02, -0.23 to 0.27, p = 0.88) in both groups (p>0.05), but co-infected participants had significantly higher LSM than mono-infected throughout follow-up (β = 0.018, 0.019-0.28, p < 0.001). Year 3 LSM differed according to ART initiation status by Year 3 (initiators - non-initiators: -0.87, -1.70 to -0.29). In this cohort, LSM remained higher among HIV-HBV co-infected versus HIV mono-infected participants throughout follow-up. Our findings emphasize the continuing need for monitoring of liver outcomes in HIV-HBV co-infected populations on ART and the importance of preventing HBV infection among PLH to optimize liver health.

S1024 Evaluation of the FAST Score in Patients With Nonalcoholic Fatty Liver Disease and High Liver Stiffness Measurements

INTRODUCTION: Liver stiffness measurement (LSM) by vibration controlled transient elastography (VCTE) has changed the management of patients with suspected nonalcoholic fatty liver disease (NAFLD) in terms of risk stratification. Patients with NAFLD and elevated LSM ≥10 kPa are considered high-risk and require further intervention including pharmacotherapy once available. Recently, the FAST score was introduced as a new method to risk stratify patients with NAFLD with patients with high FAST ≥0.67 being considered high-risk and those with FAST ≤0.35 being considered low risk. The aim of the current study was to evaluate the concordance between VCTE and the new FAST score in patients with high LSM. METHODS: Our cohort consisted of consecutive patients who presented for evaluation of fatty liver were included. All had Fibroscan to measure CAP and LSM + AST within 6 months. Only patients with high LSM ≥10 kPa were included in this analysis. The M and XL Fibroscan probes were used based on the machine’s recommendation. Nominal and continuous variables were analyzed with chi-squared and 2-sided T-tests. RESULTS: A total of 665 patients presented with suspected fatty liver, 67.6% were female, 29.8% had diabetes, 58.2% had hypertension, and 46.8% had metabolic syndrome (MetS). A total of 138 patients (20.8%) had LSM ≥10 indicating advanced fibrosis. Of these patients, only 50 (36.2%) had FAST ≥0.67 indicating concordant results. More importantly, 25 patients (18.1%) with LSM ≥10 had FAST ≤0.35 indicating discordant results. Interestingly, 24/25 (96%) of patients in this group had AST < 30 U/L. Additionally, 63 patients (45.6%) with LSM ≥10 had indeterminate FAST between 0.35-0.67. In this cohort, when comparing patients with FAST ≥0.67 to those with FAST ≤0.35, patients with elevated FAST ≥0.67 had lower platelets (231.1 vs 279.9, P = 0.01), higher ALT (104.0 vs 25.2, P < 0.01), and higher ferritin (279.4 vs 100.9, P = 0.01). There was no significant difference in gender or likelihood to have diabetes, hypertension, dyslipidemia, or metabolic syndrome (P > 0.05 for all). CONCLUSION: In patient with LSM indicating high risk for advanced fibrosis, the FAST score showed concordant results in only one third of patients and to our surprise 18% would have been considered low risk based on FAST despite having high LSM. The FAST score should not be used alone to risk-stratify patients with fatty liver especially in those with AST < 30 U/L and providers should be familiar with LSM cutoffs and interpretation.

Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease.

In non-alcoholic fatty liver disease (NAFLD), fibrosis is the strongest prognostic factor and can be assessed by non-invasive methods. We evaluated the ability of liver stiffness measurement (LSM) to predict overall survival and liver, cardiovascular and oncologic complications. We prospectively collected data on 2251 consecutive NAFLD patients (mean age 59years, male 53%, mean body mass index 28kg/m2 ) in two centres. At inclusion, all patients had LSM, clinical and biological evaluation. During follow-up, we recorded cardiovascular events, cancers, liver complications, liver transplantation and death. The primary endpoint was overall survival. Survival curves according to LSM were first performed using Kaplan-Meier method for the primary endpoint, and Aalen-Johansen method for secondary outcomes to take into account competitive risks. In a second step, a Cox proportional hazard model analysis was done to identify independent predictors of overall survival. Median follow-up was 27months [IQR: 25-38]. Fifty-five patients died and three patients had liver transplantation. Overall survival significantly decreased as baseline LSM increased. Twenty-one patients (0.9%) had a liver event, 142 (6.3%) developed cancer (excluding HCC) and 151 (6.7%) had a cardiovascular event during follow-up. By multivariable analysis, independent predictors of overall survival were as follows: baseline LSM (adjusted HR (aHR) = 2.85 [1.65-4.92], P=.0002), age (aHR=1.11 [1.08-1.13], P<.0001) and male sex (aHR=2.05 [1.17-3.57], P=.012). Patients with elevated LSM were also more likely to develop cardiovascular, and liver events but not other cancers. LSM can be used to predict survival, cardiovascular and liver complications in NAFLD patients.

Prediction of Hepatic Complications after Allogeneic Haemotopoetic Stem Cell Transplantation Using Liver and Spleen Stiffness Measurement

Rationale: Allogeneic haematopoietic stem cell transplantation (HCT) is the only curative option for a variety of malignant and non-malignant diseases and is increasingly used, even in elderly and medically unfit patients (pts). Despite advances, it is associated with considerable morbidity and mortality. Major obstacles to a successful outcome are infections and graft-versus-host-disease (GvHD) but also liver-related complications like sinusoidal obstruction syndrome (SOS). An important risk factor is a preexisting chronic liver disease. Screening includes hepatitis serology and PCR, ultrasound of the liver and liver related laboratory evaluations of transaminases, gamma-GT and bilirubin. Liver stiffness measurements (LSM) using point shear-wave elastography (pSWE) and transient elastography (TE) have emerged as non-invasive methods to detect hepatic fibrosis. In addition, controlled attenuation parameter (CAP) has good accuracy for detection and differentiation of histologically defined steatosis. Both methods have been extensively evaluated in patients with various chronic liver diseases and represent non-invasive alternatives to liver biopsy. Preliminary reports suggest a potential prognostic role for LSM in the HCT setting.Patients and Methods: Consecutive pts who underwent HCT for malignant or non-malignant diseases underwent ultrasound, liver elastography and non-invasive liver fat quantification by CAP before and post conditioning. Cut-off values of 7 kPa (LSM), 1.34 m/s (pSWE), and 248 dB/m (CAP) were defined for hepatic fibrosis and steatosis, respectively. Additionally, PNPLA3 genotyping was performed. The results were correlated with the clinical course of the pts with an observation time post-HCT of 100 days. In addition overall survival (OS) and disease relapse at one year were recorded as exploratory endpoints. Events were defined as SOS, GvHD grade II-IV, sepsis from any cause, or death. Severe liver related events were either SOS, GvHD of the liver stage 3-4, or drug induced liver injury (DILI). Competing risk models and Cox regression were used for analysis.Results: Of the 120 pts screened for the trial, 110 proceeded to receive an HCT. 4 pts were excluded from the analysis because of invalid elastography. PNPLA3 genotyping was available in 103 pts. 106 pts (median age 57 years (y), 42 females, median body mass index 24.6 kg/m²) were transplanted from a matched or mismatched unrelated (n=84) or sibling donor (n=22) for acute leukemias (n=52), lymphoma or multiple myeloma (n=19), MDS/MPN (n=31) or other diseases (n=4) using myeloablative (n=27), reduced intensity (n=23) or non-myeloablative conditioning (n=56) between 2014 and 2016. A total of 33 pts developed severe complications: non-hepatic events were sepsis in 12 pts and GvHD in 5 pts. Liver-related complications occurred in 16 pts (6 female, median age 60.5 y): n=9 SOS, n= 5 liver GvHD, and n=2 DILI. The hazard ratio was 3.2 (p = 0.0022) for patients with LSM > 7 kPa and 4.4 (p = 0.0042) with pSWE > 1.34 m/s . An analysis with SOS as an endpoint was not possible due to low incidence. However, within the subgroup with liver events (n=16) the 9 patients with SOS had higher LSM values (8.2 vs 4.6 kPa, p=0.031) and showed a trend toward higher pSWE values (1.67 vs 1.29 m/s, p=0.087). GGT at baseline differed significantly between pts with liver events and those without (p=0.020). Combining GGT > 1x ULN and LSM > 7 kPa the hazard ratio was 10.8 (p=0.0097). Pts with elevated LSM at baseline had a trend toward higher non-relapse mortality (p=0.070) and had significantly lower OS at 1 y after HCT (p=0.0038). Gender, age, type of conditioning, busulphane containing conditioning, diagnosis, HCT-CI score, CAP, and PNPLA3 genotype showed no impact on the development of severe complications or liver events, however prior stem cell therapy was strongly associated with outcome.Conclusions: Elevated liver stiffness assessed by either TE or pSWE is associated with an increased risk for liver related complications including SOS, non-relapse mortality and decreased survival after allogeneic HCT. LSM should be evaluated further as a potential additional prognostic marker in the comorbidity assessment before transplant. Pts at higher risk for liver related events could be subject to additional prophylaxis such as defibrotide for the prevention of SOS. DisclosuresFranke:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Jazz: Honoraria. Niederwieser:Miltenyi: Speakers Bureau; Novartis: Research Funding.

Non-alcoholic fatty liver disease patients attending two metropolitan hospitals in Melbourne, Australia: high risk status and low prevalence.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally, with increased rates in high-risk populations, including type 2 diabetes and obesity. The condition increases the risk of end-stage liver disease, hepatocellular carcinoma and all-cause mortality. NAFLD is asymptomatic and often remains undiagnosed as routine screening in high-risk groups is not practised. The aim of this study was to determine the rates and characteristics of NAFLD patients attending liver clinics at two Melbourne metropolitan hospitals. Liver clinics were prospectively screened for 10 consecutive months and participants with a diagnosis of NAFLD were further evaluated using pathology and imaging results obtained from medical records. Of the 2050 patients screened, 148 (7%) had NAFLD predominantly diagnosed using ultrasound (81%). NAFLD patients were obese (mean body mass index 30.7 ± 5.9 kg/m2 ), insulin resistant (median HOMA 4.2 (3.2) mmol/L) and had elevated liver enzymes (ALT median, males 47.0 (34.3), females 36.0 (28.0) U/L), and 18% of patients had liver stiffness measuring >12 kPa, suggesting a moderate probability of cirrhosis. Patients with liver stiffness measuring ≥9.6 kPa had significantly higher: glucose (median 5.5 (1.2) vs 6.2 (5.3) mmol/L, P = 0.007), aspartate aminotransferase levels (median 25.5 (26.0) vs 41.0 (62.0) u/L, P = 0.0005) and HOMA (3.1 (3.0) vs 5.4 (5.5) mmol/L, P = 0.040). NAFLD constituted a minority of liver clinic patients, most of who were obese, insulin resistant and hypertensive, and many had an elevated liver stiffness measurement. NAFLD poses added adverse health outcomes to high-risk patients, and therefore, early detection is warranted.

Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: Genetic and metabolic risk factors in a general population.

The worldwide spread of obesity is leading to a dramatic increase in the prevalence of nonalcoholic fatty liver disease (NAFLD) and its complications. We aimed to evaluate both prevalence and factors associated with NAFLD in a general population in a Mediterranean area. We considered 890 consecutive individuals included in the community-based ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study (ISRCTN15840340). Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were measured with FibroScan. Participants were genotyped for PNPLA3 rs738409 and TM6SF2 rs58542926 variants. The prevalence of NAFLD in the cohort was 48%. NAFLD participants exhibited elevated LSM values, suggesting advanced fibrosis (6.5% of cases). Both NAFLD and advanced fibrosis were independently associated with traditional risk factors (NAFLD: age >50years, obesity, hypertension, elevated ALT and low HDL-cholesterol serum concentrations. Advanced fibrosis: IFG/diabetes, elevated ALT serum concentrations). A high prevalence (>60%) of NAFLD was found in obese people, while it varied widely in non-obese people according to the presence of metabolic risk factors. PNPLA3G variant (OR=1.33, 95% C.I.=1.01-1.8; P<.05) was independently associated with NAFLD. Prevalence of advanced fibrosis (high LSM values) ranged from 3.4% (no risk factors) to 60% (presence of all risk factors). TM6SF2 T variant (OR=3.06, 95% C.I.=1.08-8.65, P<.05) was independently associated with advanced fibrosis (high LSM values). In a cohort of a general population, the prevalence of NAFLD was very high, and among NAFLD patients a significant proportion had advanced fibrosis (high LSM values). Apart from traditional risk factors, genetic factors may have a significant role that needs to be further investigated.

Liver stiffness measurement in the primary care setting detects high rates of advanced fibrosis and predicts liver-related events in hepatitis C

As many as 70% of individuals with chronic hepatitis C (CHC) are managed solely in primary care. The aims of this study were to determine the prevalence of elevated liver stiffness measurement (LSM) in a cohort of community managed patients with CHC and to evaluate predictors of advanced liver disease and liver-related events. A prospective cohort of adult patients with CHC were recruited from 21 primary care practices throughout Victoria, Australia. Inclusion criteria included the presence of CHC for >6 months, no recent (<18 months) specialist input and no history of hepatocellular carcinoma. Clinical assessment, LSM and phlebotomy were carried out in primary care. A hospital cohort was recruited for comparison. Participants were followed longitudinally and monitored for liver-related events. Over 26 months, 780 community patients were recruited and included in the analysis. The median LSM was 6.9 kPa in the community, with 16.5% of patients at risk of advanced fibrosis (LSM ≥12.5 kPa); of these 8.5% had no laboratory features of advanced liver disease. The proportion at risk of cirrhosis was no different between the community and hospital cohorts (p = 0.169). At-risk alcohol consumption, advancing age, elevated body mass index and alanine aminotransferase were independent predictors of elevated LSM. Over a median follow-up of 15.2 months, liver-related events occurred in 9.3% of those with an LSM ≥12.5 kPa. An LSM of 24 kPa had the highest predictive power for liver-related events (hazard ratio152; p <0.001). The prevalence of advanced fibrosis, as determined by LSM, in primary care managed CHC is significant and comparable to a hospital cohort. Furthermore, this study supports the use of LSM as a community screening tool in a CHC population and indicates a possible role in predicting liver-related events. The prevalence of advanced liver disease in primary care managed hepatitis C is unknown. Our data suggests that rates of advanced fibrosis in the community are significant (16.5%), often underdiagnosed and comparable to rates seen in specialist referral centres. Liver stiffness measurement is a feasible community screening tool prior to hepatitis C therapy and can predict liver-related adverse events.

Potential impact of screening for fatty liver disease by transient elastography with liver stiffness and controlled attenuation parameter measurements: a pilot study.

Background The prevalence of chronic liver diseases is high in developed countries, and the leading causes are amenable to prevention. The German Lebertag is to increase awareness of the burden of chronic liver diseases in the general public. We performed a pilot study using transient elastography with liver stiffness measurement (LSM) and the controlled attenuation parameter (CAP) as a screening tool for previously unrecognized liver diseases. Patients and methods LSM and CAP was performed in 60individuals,and participants filled in a questionnaire reporting basic characteristics and past medical history. Results Median LSM and CAP values were within the normal range. Participants with self-reported diabetes mellitus had significantly elevated LSM (p = 0.02) and CAP values (p = 0.002). Participants with a BMI > 30 kg/m2 or dyslipidemia had significantly elevated CAP values (p = 0.007 and p = 0.01, respectively) with normal LSM values. Overall, 35 % of participants had elevated CAP values, indicating a high prevalence ofhepatic steatosis. Discussion In a German pilot study, diabetes mellitus was a key risk factor for increased LSM and CAP values. Prevalence of steatosis was high and comparable to other Western countries. Transient elastography is a valuable tool to identify patients with increased risk for metabolic liver diseases. In people without risk factors, LSM and CAP values were within the normal range, indicating that screening for chronic liver injury was not warranted.

Abnormal Liver Stiffness Measurement in a Patient with Waldenstrom Macroglobulinemia: Nuances in Interpreting the Findings

Background: Liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE) provides an estimate of liver fibrosis, non-invasively, in a quick and efficient manner. Its use and interpretation of LSM is limited. In the current case, we report our findings of abnormal LSM and liver histology in a patient with Waldenstrom Macroglobulineima (WM) with evidence of portal hypertension. Case: A 84-year-old white man with history notable for WM and history of pulmonary embolism on chronic anticoagulation presented with new-onset ascites. His blood work revealed isolated elevation in alkaline phosphatase (AST 14 U/L, ALT 7 U/L, ALP 173 U/L, GGT 275 u/L and total bilirubin 0.6 mg/dL) with a platelet count was 208 k/cumm. Blood work for competing etiology was negative for viral, metabolic, and autoimmune hepatitis (negative viral hepatitides, normal iron studies, normal alpha-1-antitrypsin level, negative anti-smooth muscle antibody and negative anti-mitochondrial antibody with normal immunoglobulins (other than presence of IgM kappa monoclonal protein) ruling out primary biliary cirrhosis). Ultrasound with dopplers showed cirrhotic appearing liver, cholelithiasis, mild ascites not amenable to diagnostic paracentesis, and patent portal veins. MRCP showed normal appearing liver, mild ascites, and gallbladder sludge without biliary dilation. Evaluation with VCTE after paracentesis revealed elevated LSM at 12.2 with IQR% of 9%. Pressure measurements during transjugular liver biopsy noted normal hepatic vein pressure gradient (HVPG) of 6 mmHg (corrected sinusoidal pressure 10 mmHg (RA 1 mmHg, IVC 5 mmHg, free HV 5 mmHg, wedge 11 mmHg), consistent with pre-sinusoidal portal hypertension. Liver histology showed nodularity in the absence of significant fibrosis. Reticulin stain confirmed nodularity and showed areas of hepatic trabecular compression and others with trabecular thickening. Focal mild sinusoidal dilatation was seen. The portal tracts are largely unremarkable with patchy mild chronic inflammation and minimal ductular reaction. Congo red stain was negative as well ruling out amyloidosis. Conclusion: This case highlights the rare presentation of non-cirrhotic portal hypertension with WM and the false increase in LSM due to infiltration with M protein.